Alzheimer's disease is a severe neurodegenerative disorder, and currently about 4 million Americans suffer from this disease. As the aging population continues to grow, this number could reach 14 million by the middle of next century unless a cure or prevention is found. At present, there is no sensitive and specific premortem test for early diagnosis of this disease. Alzheimer's disease is currently diagnosed based on the clinical observation of cognitive decline, coupled with the systematic elimination of other possible causes of those symptoms. The confirmation of the clinical diagnosis of “probable Alzheimer's disease” can only be made by examination of the postmortem brain. The Alzheimer's disease brain is characterized by the appearance of two distinct abnormal proteinaceous deposits in regions of the brain responsible for learning and memory (e.g., cerebral cortex and hippocampus). These deposits are extracellular amyloid plaques, which are characteristic of Alzheimer's disease, and intracellular neurofibillary tangles (NFTs), which can be found in other neurodegenerative disorders as well. Amyloid peptides are typically either 40 or 42 amino acids in length (“Aβ1-40” or “Aβ1-42”, respectively) and are formed from abnormal processing of a larger membrane-associated protein of unknown function, the amyloid precurser protein (“APP”). Oligomeric aggregates of these peptides are thought to be neurotoxic, eventually resulting in synaptic degeneration and neuronal loss. The amount of amyloid deposition roughly correlates with the severity of symptoms at the time of death.
In the past, there have been several attempts for the design of radiopharmaceuticals that could be used as diagnostic agents for a premortem diagnosis of Alzheimer's disease.
Bomebroek et al. showed that the amyloid-associated protein serum amyloid P component (SAP), labeled with 123I, accumulates at low levels in the cerebral cortex, possibly in vessel walls, of patients with cerebral amyloidosis (Bomebroek, M., et al., Nucl. Med. Commun. (1996), Vol. 17, pp. 929-933).
Saito et al. proposed a vector-mediated delivery of 125I-labeled Aβ1-40 through the blood-brain barrier. It is reported that the iodinated Aβ1-40 binds Aβ amyloid plaque in tissue sections (Saito, Y., et al., Proc. Natl. Acad. Sci. USA 1995, Vol. 92, pp. 10227-10231).
U.S. Pat. No. 5,231,000 discloses antibodies with specificity to A4 amyloid polypeptide found in the brain of Alzheimer's disease patients. However, a method to deliver these antibodies across the blood-brain barrier has not been described.
Zhen et al. described modifications of the amyloid-binding dye known as “Congo Red™”, and complexes of these modified molecules with technetium and rhenium. The complexes with radioactive ions are purported to be potential imaging agents for Alzheimer's disease (Zhen et al., J. Med. Chem.(1999), Vol. 42, pp. 2805-2815). However, the potential of the complexes to cross the blood-brain barrier is limited.
A group at the University of Pennsylvania in the U.S.A. (Skovronsky, M., et al., Proc. Natl. Acad. Sci. 2000, Vol. 97, pp. 7609-7614) has developed a fluorescently labeled derivative of Congo Red that is brain permeable and that non-specifically binds to amyloid materials (that is, peptides in β-pleated sheet conformation). This compound would need to be radiolabeled and then run through pre-clinical screens for pharmacokinetics and toxicity before clinical testing.
Klunk et al. reported experiments with a derivative of Congo Red™, Chrysamine G (CG). It is reported that CG binds synthetic β-amyloid well in vitro, and crosses the blood-brain barrier in normal mice (Klunk et al., Neurobiol. Aging (1994), Vol. 15, No. 6, pp. 691-698).
Bergström et al. presented a compound labeled with iodine-123 as a potential radioligand for visualization of M1 and M2 muscarinic acetylcholine receptors in Alzheimer's disease (Bergström et al., Eur. J. Nucl. Med. (1999), Vol. 26, pp. 1482-1485).
Recently, it has been discovered that certain specific chemokine receptors are upregulated in the brains of patients with Alzheimer's disease (Horuk, R. et al., J. Immunol. (1997), Vol. 158, pp. 2882-2890); Xia et al., J. NeuroVirol. (1999), Vol. 5, pp. 32-41). In addition, it has been shown recently that the chemokine receptor CCR1 is upregulated in the brains of patients with advanced Alzheimer's disease and absent in normal-aged brains (Halks-Miller et al, CCR1 Immunoreactiviy in Alzheimer's Disease Brains, Society for Neuroscience Meeting Abstract, #787.6, Volume 24, 1998). Antagonists to the CCR1 receptor and their use as anti-inflammatory agents are described in the PCT Published Patent Application, WO 98/56771.
None of the above described proposals have resulted in a clinical development of an imaging agent for the early diagnosis of Alzheimer's disease. Accordingly, there is still a clinical need for a diagnostic agent that could be used for a reliable and early diagnosis of Alzheimer's disease.